Two diffusion-based approaches, CG (constant gradient) and FEXI (filtered exchange imaging) methods, have been previously proposed for measuring transcytolemmal water exchange rate constant k, but their accuracy and feasibility have not been comprehensively evaluated and compared. In this work, both computer simulations and cell experiments in vitro were performed to evaluate these two methods. Simulations were done with different cell diameters (5, 10, 20μm), a broad range of k values (0.02-30s) and different SNR's, and simulated k's were directly compared with the ground truth values. Human leukemia K562 cells were cultured and treated with saponin to selectively change cell transmembrane permeability. The agreement between measured k's of both methods was also evaluated. The results suggest that, without noise, the CG method provides reasonably accurate estimation of k especially when it is smaller than 10s, which is in the typical physiological range of many biological tissues. However, although the FEXI method overestimates k even with corrections for the effects of extracellular water fraction, it provides reasonable estimates with practical SNR's and more importantly, the fitted apparent exchange rate AXR showed approximately linear dependence on the ground truth k. In conclusion, either CG or FEXI method provides a sensitive means to characterize the variations in transcytolemmal water exchange rate constant k, although the accuracy and specificity is usually compromised. The non-imaging CG method provides more accurate estimation of k, but limited to large volume-of-interest. Although the accuracy of FEXI is compromised with extracellular volume fraction, it is capable of spatially mapping k in practice.
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